Project Abstract Major limb amputation affects millions of people worldwide. Following amputation, all most all patients have phantom limb sensations (PLS) and over 85% develop phantom limb pain (PLP). Despite its documented existence for several hundred years, the etiology of PLP remains unknown. The three principal theories are cortical reorganization, a mismatch between visual and proprioceptive feedback, and proprioceptive memory. Experimental evidence demonstrates that cortical maps representing a limb within sensorimotor cortex reorganize following limb amputation. A correlation exists between the amount of cortical reorganization in upper extremity amputees and the severity of PLP. We have recently demonstrated that mirror therapy can relieve PLP in unilateral lower extremity amputees, but the physiological basis remains unknown. Our principal hypothesis is that, rather than simple cortical reorganization, rapid, but reversible changes, in addition to delayed changes, occur in the cortical network connecting various brain regions, leading to the development of PLS and PLP. We will assess whether dynamic changes in connectivity following upper limb deafferentation and manifest as PLS or PLP with proprioceptive memories, what changes there are in cortical network connectivity (using fMRI) to assess changes in brain activation patterns before and after visual feedback from mirror therapy, and determine if differential mechanisms underlie rapid and delayed dynamic functional changes in cortical networks following permanent forelimb deafferentation (amputation or brachial plexus nerve cut) and transient inactivation (brachial plexus anesthesia) using a rodent model to mimic changes observed in humans. These studies will not only enable us to better understand the physiological basis of the interaction of the visual system, cortical reorganization and network connectivity, and the development of PLP but will also contribute to the development of a functional measure of the response of PLP to treatment and may result in the development of additional treatments for PLP for both female and male amputees.